1. Field of the Invention
The present invention relates generally to health care diagnostics and specifically to a method and a test kit for non-invasive, non-instrumented oral sampling in a human subject utilizing the collection of fluid from the mouth and/or pharynx of the patient. Fluid obtained from the mouth through rinsing, and/or from the pharynx (throat area) through gargling, is collected; analysis of the characteristic of interest in the fluid is performed in the specified collection device, providing a rapid result without manual handling of the fluid sample. The methods of the invention are suitable for a self-test (test performed in the home) and as a point-of-care test performed by the health professional to provide a rapid result in a clinical setting. The methods of the invention may be applied to any characteristic of the mouth and/or pharynx which can be sampled by rinsing and/or gargling, retrieving the resulting fluid in a specified collection container or device and then analyzing the fluid in the collection container or device to provide a rapid or point-of-care result.
More particularly, the present invention provides methods and a test kit for non-invasive, non-instrumented assessment and diagnosis of the condition of acid reflux by sampling of the pharynx through the gargling process, and rapid determination of the pH of the collected fluid.
The use of diagnostic procedures or tests which provide rapid results in the health professional's office (point-of-care testing) has become an important component of medical practice. Such procedures are typically non- or minimally-invasive, require limited or no instrumentation and allow for efficient and cost-effective diagnosis. The development of rapid, non-invasive and non-instrumented technologies has increased the availability of consumer "home test" kits, allowing for layperson self-testing to identify important health conditions (e.g., pregnancy, blood in the stool, elevated cholesterol) and to promote appropriate and timely use of health care resources.
Gastroesophageal or acid reflux (hereinafter referred to as acid reflux) is the retrograde movement of acidic contents of the stomach into the esophagus and beyond. The body manages minor amounts of acid reflux, which are common in normal gastrointestinal function, by mechanical movement back toward the stomach in the normal direction of ingested food and liquid (known as peristalsis) and by neutralization by bicarbonate sources, including saliva (Singh, S. et al., "Determinants of esophageal `alkaline` pH environment in controls and patients with gastroesophageal reflux disease," Gut, March 1993; 34 (3): 309-16). As a result, the pH levels of tissues affected by minor amounts of acid reflux are maintained at normal levels. However, increased amounts of acid reflux overwhelm these corrective factors, resulting in greater acidity of affected tissues and the resulting symptoms of acid reflux. While the lining of the stomach is normally able to resist the adverse effects of stomach acid, this is not the case for tissues contacted by acid reflux including the esophagus and pharynx. Reduced saliva volume and/or neutralization potential can contribute to increased acidity of the pharynx during periods of sleep (known as nocturnal pharyngeal acidification).
Acid reflux is considered to be the most common inflammatory disorder of the upper gastrointestinal tract (Chen, M., et al., "Gastroesophageal reflux disease: correlation of esophageal pH testing and radiographic findings," Radiology, 1992; 185: 483-6) and is estimated to affect over 15 million Americans on a daily basis, and 40% of the population on a monthly basis (Kahrilas, P., "Gastroesophageal reflux disease," JAMA. Sep. 25, 1996 25; 276(12): 983-8 and American College of Gastroenterology, 1997). Acid reflux occurs most frequently within the first 3 hours after food intake (Schoeman et al., "Mechanisms of gastroesophageal reflux in ambulant healthy human subjects," Gastroenterology, January 1995; 108(1): 83-91). Exposure of tissues to acid reflux results in symptoms including regurgitation, heartburn and sore throat and may lead to tissue damage. Symptoms and tissue damage caused by acid reflux are referred to in the medical profession as gastroesophageal reflux disease (GERD).
The occurrence of extraesophageal effects of acid reflux (effects outside the esophagus, i.e., in the pharynx or throat) due to acid reflux reaching to this area is increasingly being recognized in the medical community today (Chen et al, 1992, supra; Richter, J., "Extraesophageal presentations of gastroesophageal reflux disease," Semin. Gastrointest. Dis. April 1997; 8(2): 75-89; and Wall Street Journal, "When your heartburn starts to linger after the holidays," Dec. 29, 1997). This causes various problems including hoarseness, laryngitis and chronic cough (Wiener, G., et al., "Chronic hoarseness secondary to gastroesophageal reflux disease: documentation with 24-hour ambulatory pH monitoring," Am J Gastroenterol., 1989; 84(12): 1503-8; Contencin, P., and Narcy, P., "Gastroesophageal reflux in infants and children: A pharyngeal pH monitoring study," Arch. Otolaryngol. Head Neck Surg., October 1992; 118:1028-30; Pope, C., "Acid-reflux disorders," N. Engl. J. Med., Sep. 8. 1994; 331(10): 656-60; and Kahrilas, 1996, supra). Because it may at times reach the mouth, acid reflux has been observed to have effects on this area as well (Meurman, J., et al., "Oral and dental manifestations in gastroesophageal reflux disease," Oral Surg. Oral Med. Oral Pathol., November 1994; 78(5): 583-9; Schroeder, P., et al., "Dental erosion and acid reflux disease," Ann. Intern. Med., Jun. 1, 1995; 122(11): 809-15; and Madinier, I., et al., "Oral carriage of Helicobacter pylori: a review," J. Periodontol., January 1997; 68(1):2-6). The occurrence of acid reflux reaching the pharynx and altering the pH of contacted tissues provides a basis for sampling of the pharynx to detect the acid reflux condition. Prior to the present invention, only instrumented, invasive methods were available to detect acid reflux.
Acid reflux causes a reduction in pH (increased acidity) of affected tissues. Detection of the pH of these tissues, including the esophagus and pharynx, provides a means for objective diagnosis of acid reflux states. Measurement of pH in the esophagus or pharynx using invasive instruments (the sole method of pH measurement in acid reflux until the present invention) has determined that decreased pH (or greater acidity) is associated with acid reflux and that decreased pH increases the risk of complications of acid reflux including esophageal erosion, laryngitis and chronic cough (Schindlbeck, N., et al., "Which pH threshold is best in esophageal pH monitoring?" Am. J. Gastroenterol., 1991; 86(9): 1138-41; Chen et al., 1992, supra; Orr, W., et al., "The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage," Am. J. Gastroenterol., April 1994; 89(4): 509-12; Jacob, P., et al., "Proximal esophageal pH-metry in patients with reflux laryngitis," Gastroenterology 1991; 100: 305-10; Shaker, R., et al., "Esophagopharyngeal distribution of refluxed gastric acid in patients with reflux laryngitis," Gastroenterology 1995; 109: 1575-82; and Vaezi, M., and Richter, J., "Twenty-four hour ambulatory esophageal pH monitoring in the diagnosis of acid reflux-related chronic cough," South Med.J., March 1997; 90(3): 305-11). Using instrument monitoring, 50 percent of adult ear-nose-throat patients and 93 percent of children with respiratory conditions were found to have abnormal amounts of acid reflux reach to the level of the pharynx (Koufman, J., and Cummins, M., "The prevalence and spectrum of reflux in laryngology: a prospective study of 132 consecutive patients with laryngeal and voice disorders," Center for Voice Disorders of Wake Forest University, 1997).
The majority of persons with acid reflux symptoms do not seek professional medical evaluation and engage in self-treatment with widely-available over-the-counter medications (Locke III, G., et al., "Prevalence and clinical spectrum of gastroesophageal reflux: A population-based study in Olmsted County, Minn.," Gastroenterology, 1997; 112: 1448-56). These medications include antacids and drugs to reduce stomach acid production. However, while symptoms of acid reflux can be intermittent and may respond to over-the-counter medications, the condition often requires professional medical evaluation and treatment (Isolauri, J., et al., "Natural course of gastroesophageal reflux disease: 17-22 year follow-up of 60 patients," Am. J. Gastroenterol., January 1997; 92(1): 37-41). Perceived symptoms can be an unreliable indicator of the presence and extent of acid reflux (Olden, K., and Triadafilopoulos, G., "Failure of initial 24-hour esophageal pH monitoring to predict refractoriness and intractability of reflux esophagitis," Am. J. Gastroenterol., 1991; 86(9): 1142-6; Jamieson, J., et al., "Ambulatory 24-hour esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity, and reproducibility," Am. J. Gastroenterol., 1992; 87(9): 1102-1110; and Tew, S., et al., "The illness behavior of patients with gastroesophageal reflux disease with and without endoscopic esophagitis," Dis. Esophagus., January 1997; 10(1): 9-15). Without benefit of objective assessment, symptoms of acid reflux may be confused with other gastrointestinal conditions or other health problems which require professional medical evaluation, such as chest pain.
Effective acid reflux treatment requires accurate diagnosis. Many persons do not experience sufficient acid reduction with over-the-counter treatments and doses and therefore should receive medical evaluation and prescription medication (Bardhan, K., "Is there any acid peptic disease that is refractory to proton pump inhibitors?" Aliment. Pharmacol. Ther., 1993; 7 Suppl 1: 13-24). The class of acid reflux prescription medications known as proton pump inhibitors can render superior results in treatment of acid reflux (Loughlin, C., and and Koufman, J., "Paroxysmal laryngospasm secondary to gastroesophageal reflux," Laryngoscope, December 1996; 106(12 Pt. 1):1502-1505; Kahrilas, 1996, supra; Sachs, G., "Proton pump inhibitors and acid-related diseases," Pharmacotherapy January-February 1997; 17(1): 22-37; Sontag, S., et al., "Lansoprazole heals erosive reflux esophagitis resistant to histamine H2-receptor antagonist therapy," Am. J. Gastroenterol., March 1997; 92(3): 429-37; and Koufman and Cummins, 1997, supra). Eighty-five percent of persons with laryngitis caused by acid reflux respond to omeprazole, a type of proton pump inhibitor (Shaw, G., et al., "Subjective, laryngoscopic, and acoustic measurements of laryngeal reflux before and after treatment with omeprazole," J. Voice., December 1996; 10(4): 410-8). To ensure appropriate use of health care resources and effective treatment of acid reflux conditions, objective diagnosis is needed. Yet because of the limitations of current diagnostic methods, which involve invasive instruments, require prolonged testing and cannot be easily repeated, the large proportion of the general population which suffers with acid reflux is precluded from objective diagnostic evaluation (DeVault, K. and Castell, D., "Guidelines for the diagnosis and treatment of gastroesophageal reflux disease," Arch. Intern. Med., 1995; 155(20): 2165-2173).
What is therefore needed in the art is a non-invasive, non-instrumented means of objective detection of acid reflux which provides rapid results as a point-of-care diagnostic test. Such a test could be used by medical professionals for cost-effective screening of patients for acid reflux, bringing the benefits of objective diagnosis of acid reflux to the general population. These test characteristics would also provide the means for a self-test, as test procedures would not require professional assistance. Such a test could be used to enhance self-treatment, by assisting the layperson in evaluating the cause of symptoms, tracking response to treatment and identifying a need for professional medical evaluation. Such a test would be well received in the medical community and consumer market for self-testing. The expanding array of over-the-counter options for self-treatment of acid reflux, which in the future may include potent proton-pump inhibitors, further points to the importance of objective assessment of this condition to ensure appropriate treatment and professional medical evaluation when indicated.
2. Description of the Prior Art
Previous studies have used invasive instruments to measure the pH of the pharynx area to detect acid reflux. Instrument-based pH monitoring of the pharynx has shown results in a pH range of around 5 to 7.5 (Haase, G., et al., "A unique teletransmission system for extended four-channel esophageal pH monitoring in infants and children," J. Ped. Surg., January 1987; 22(1): 68-74; Contencin, P., et al., "Measurement of pH of the rhinopharynx in children with gastroesophageal reflux," Presse Medicale, 1989; 18(1): 13-6; Wiener et al, 1989, supra; and Chen et al, 1992, supra). Instrument-based pH testing during surgery determined that individual pharynx pH rarely varied by more than 1.0 pH unit in the absence of regurgitation (Joshi, G., et al., "Continuous hypopharyngeal pH measurement in spontaneously breathing anesthetized outpatients: laryngeal mask airway versus tracheal intubation," Anesth. Analg., 1996; 82: 254-7). No previous studies have considered the gargling method for detecting acid reflux. Furthermore, no prior medical literature or patents have described the collection of fluid from gargling and measurement of the pH of this fluid, within a collection container or device as a means of evaluating for presence of acid reflux.
Several patents disclose methods involving the placement of devices in the oral cavity to obtain an oral sample for testing. See, for example, U.S. Pat. No. 4,114,605, "Intraoral cup for collecting saliva and method of using the same" (McGhee et al.), U.S. Pat. No. 4,418,702, "Method and apparatus for collecting saliva" (Brown et al.), U.S. Pat. No. 5,103,386, "Oral collection device and kit for immunoassay" (Goldstein et al.), U.S. Pat. No. 5,339,829, "Oral collection device" (Thieme et al.), U.S. Pat. No. 5,479,937, "Oral collection device" (Thieme et al.), U.S. Pat. No. 5,563,073, "Personal blood alcohol level testing kit" (Titmas, T.) and U.S. Pat. No. 5,573,009, "Oral sample collection method" (Thieme et al.).
One published study discusses collecting the fluid from gargling for subsequent laboratory analysis of collected tissue cells for evidence of malignancy (Ayre, J., "The gargle test: new oral cancer screening method," N.Y. State Dent. J., June-July 1972; 38(6): 345-50).
Other literature describes gargling to obtain a sample of fluid for subsequent laboratory identification of the types and quantities of microbial organisms present in the pharynx.
U.S. Pat. No. 4,321,251, "Detection of malignant lesions of the oral cavity utilizing toluidine blue rinse," (Mashberg, March, 1982) describes a method of rinsing and gargling with a specified solution to detect a color change within the mouth, for detection of malignant oral lesions.
U.S. Pat. No. 4,397,944, "Compositions for diagnosis of dental caries activity," (Komura, 8/83) describes a method of detecting the pH of dental plaque placed in a specified solution, using bromothymol blue or other coloring agents.
U.S. Pat. No. 5,022,409, "Oral rinse immunoglobulin collection kit for immunoassay and method thereof" (Goldstein et al.) discloses a method of rinsing the mouth to collect an oral sample for subsequent storage and transport for testing.